Alzheimer's disease is a debilitating degenerative affliction of the nervous system, which will become increasingly common during the next three decades as the American population ages. In the baby-boomer generation in particular, has aged. Current estimates reveal that by 2035, when the average individual of the “baby boomer” generation is age 85, potentially 50% of Americans will have developed Alzheimer's disease. By providing a treatment that can delay the onset of symptoms of Alzheimer's by as little as five years, at age 85, fifty percent of the United States cases of Alzheimer's could be eliminated. Alzheimer's disease has a negative impact on an individual's memory and cognitive functions, ability to perform the simple activities of daily living, and causes behavioral problems among its sufferers with which families must learn to cope. Typically, Alzheimer's disease also reduces the lifespan of an individual by increasing one's risk of succumbing to secondary infections and illnesses. The disease is associated with the accumulation of β-amyloid plaques in the brain which leads to the eventual destruction of brain cells. The primary cause of Alzheimer's disease may be flaws in the metabolic processes governing production, accumulation, or disposal of the β-amyloid protein fragments. Therefore, treatments for Alzheimer's disease often have focused on dissolving β-amyloid or preventing the aggregation of the β-amyloid fragments into plaque formations.
Recent research has shown that people indigenous to the Indian subcontinent exhibit a much lower incidence of Alzheimer's disease than people living in the United States. Moreover, the research indicated that less than one percent of individuals in the examined population on the Indian subcontinent developed Alzheimer's and that the overall incidence rates of the disease in that location are among the lowest ever reported. V. Chandra et al., Incidence of Alzheimer's disease in a rural community in India: the Indo-US study, Neurology, 57(6): 985-989 (2001). Some researchers have attributed the low incidence of Alzheimer's disease in India to regional diets that are high in the curry spice, turmeric. Turmeric contains a substance, curcumin, which has demonstrated metabolic activity similar to non-steroidal anti-inflammatory drugs. Giselle P. Lim et al., The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse, Journal of Neuroscience, 21(21), 8370-8377 (2001).
Curcumin, a phenolic antioxidant phytochemical derived from the turmeric plant (Curcuma longa), is an effective antioxidant, antispasmodic, anti-inflammatory, anticoagulant, anticarcinogenic, and aids immunomodulatory activities and wound healing in the body. Id. at 8370. Curcumin exhibits an affinity for β-amyloid and both inhibits the aggregation of β-amyloid fragments into plaque formations as well as dissolves existing β-amyloid plaques. F. Yang et al., Curcumin inhibits formation of Aβ oligomers and fibrils, binds plaques and reduces amyloid in vivo, Journal of Biological Chemistry (2004).
As an antioxidant, curcumin removes harmful free radicals from the body, thereby protecting the human body, and particularly, the brain, by preventing lipid peroxidation. This antioxidant property of curcumin limits the formation and accumulation of β-amyloid plaques within the brain. Giselle P. Lim et al., The Curry Spice Curcumin Reduces Oxidative Damage and Amyloid Pathology in an Alzheimer Transgenic Mouse, Journal of Neuroscience, 21(21), at 8370 (2001). The non-steroidal anti-inflammatory activity of curcumin includes inhibiting cyclooxygenase 2, nuclear factor κB-mediated transcription of inflammatory cytokines, and the inhibition of inducible nitric oxide synthase. Id. at 8372. Research has shown that parenteral administering both low and high doses of curcumin reduces inflammation in the brain. Id. at 8373. Curcumin may also stimulate microglial phagocytosis of amyloid in the brain as well as destroy plaques that accumulate within the brain. Id. at 8375.
One disadvantage to the use of curcumin as an oral dietary supplement is that curcumin is poorly absorbed from inside the gastrointestinal tract into the human bloodstream. When ingested, curcumin normally remains in the gastrointestinal tract and uptake into the bloodstream is negligible. R. A. Sharma, Preclinical pharmacokinetic study of dietary curcumin and its effects on biomarkers of cancer chemoprevention, Clinical Cancer Research, Volume 6 (2000). Even with high dietary intake, curcumin is rapidly glucuronidated after ingestion, thereby resulting in low plasma levels of curcumin. F. Yang et al., Curcumin inhibits formation of Aβ oligomers and fibrils, binds plaques and reduces amyloid in vivo, Journal of Biological Chemistry, p. 22 (2004). Thus, current research indicates that orally administered curcumin, for the most part, is excreted in the feces without being absorbed and processed by the human body. To make available the beneficial effects of curcumin to Alzheimer's sufferers, the bioavailability of curcumin in the human body must be increased. Currently, clinical trials are being conducted at the University of California, Los Angeles, to examine the safety and tolerability of intravenous curcumin, and to determine the effect curcumin has as a treatment for patients suffering from mild to moderate Alzheimer's disease. John Ringman & Jenny Bardens, A Phase II, Double-Blind, Placebo-Controlled Study of the Safety and Tolerability of Two Doses of Curcumin C3 Complex versus Placebo in Patients with Mild to Moderate Alzheimer's Disease, National Institutes of Health, ClinicalTrials.gov (2003).
Piperine, a botanical extract from the fruits of Piper nigrum (black pepper) and Piper longum, has been determined to increase the bioavailability of curcumin in the body when both curcumin and piperine are taken together. Studies have shown that oral administration of 20.0 mg of piperine with 2.0 grams of curcumin increases the bioavailability of curcumin by 2,000%. U.S. Pat. No. 6,054,585, issued to Majeed et al., on Apr. 25, 2000, describes a process for making high-purity piperine from black pepper or long pepper for nutritional uses, however the '585 patent does not discuss the use of curcumin with piperine as a means for retarding the onset of Alzheimer's disease. U.S. Pat. Nos. 5,536,506, 5,744,161, and 5,972,382, issued to Majeed et al., on Jul. 16, 1996, Apr. 28, 1998, and Oct. 26, 1999, respectively, all describe the use of piperine as a bioavailability enhancer for aiding and improving gastrointestinal absorption and systemic utilization of nutrients and nutritional supplements. The use of piperine to enhance the bioavailability of curcumin and other beneficial substances, which are not easily absorbed by the human gastrointestinal tract, is claimed by the '506, '161, and '382 patents, however, none of the three prior art patents mention the use of piperine for enhancing the bioavailability of curcumin to retard the onset of symptoms of Alzheimer's disease in humans as claimed by the applicant's current patent application.
Galantamine, a natural plant extract derived from the daffodil, snowdrop, and the spider lily, is an acetylcholinesterase inhibitor. Acetylcholinesterase is an enzyme that breaks down acetylcholine in the synaptic cleft between nerve cells. Acetylcholine is involved in memory and learning processes. Research has shown that the level of acetylcholine present in the nervous system of Alzheimer's patients is abnormally low. Galantamine increases the level of acetylcholine present in the brain by inhibiting the activity of acetylcholinesterase. In addition to being a useful therapeutic agent in the treatment of Alzheimer's disease, galantamine may also be useful for treating mild cognitive impairment, an age-related condition often diagnosed as a precursor condition and risk factor for developing Alzheimer's. Galantamine is also effective in treating Alzheimer's disease because it works to modulate nicotinic receptors on brain cells, which respond to acetylcholine, thereby preserving the number and functional integrity of nicotinic receptors in the brain. In Alzheimer's patients, the number and functional integrity of nicotinic receptors is diminished resulting in fewer receptors for acetylcholine. The benefits of treating Alzheimer's with galantamine are not affected by previous treatments using other acetylcholinesterase inhibitors. Thus, galantamine may work to effectively halt the progression of Alzheimer's disease and also allows a patient to regain some memory and cognitive functions as well as being able to perform some simple tasks of daily living. None of the three prior art patents mention the use of piperine for enhancing the bioavailability of galantamine to retard the onset of symptoms of Alzheimer's disease in humans as claimed by the applicant's current patent application.
Huperzine A, an alkaloid plant extract from the club moss Huperzia serrata, is a nootropic agent that also strongly inhibits the activity of acetylcholinesterase. As huperzine A inhibits the breakdown of acetylcholine by acetylcholinesterase, more acetylcholine becomes available to stimulate neurons. Huperzine A provides a long-lasting, potent means for inhibiting the enzymatic activity of acetylcholinesterase, thereby increasing the amount of acetylcholine present within the nervous system. The prior art does not describe the use of piperine for enhancing the bioavailability of huperzine A to retard the onset of symptoms of Alzheimer's disease in humans as claimed by the applicant's current patent application.
Oleic acid increases the absorptivity of the intestines so that food and nutrients can be fully absorbed into the body. In this way, oleic acid aids the body in digesting and processing substances that are difficult to digest. Bile (phosphatidylcholine) is the body's principle source of oleic acid in the small intestine, however only small amounts are produced. Oleanolic acid and ursolic acid share similar properties with oleic acid and also enhance the effects of curcumin in the body. The prior art, including the United States patents discussed above, does not describe the use of piperine for enhancing the bioavailability of oleic acid to retard the onset of symptoms of Alzheimer's disease in humans as claimed by the applicant's current patent application.
Pyritinol is a vitamin B6 derivative that improves glucose uptake within the brain, has antioxidant abilities, and enhances the immune system by increasing neutrophil activity. The Food and Drug Administration approved pyritinol for use to improve memory, concentration, and vigilance. Once again, the prior art does not describe the use of piperine for enhancing the bioavailability of pyritinol to retard the onset of symptoms of Alzheimer's disease in humans as claimed by the applicant's current patent application.
Vinpocetine is another drug that has shown memory-enhancing properties in humans. Vinpocetine is believed to enhance blood flow in the brain, safeguard brain cells against damage, and inhibit the activity of a substance known as phosphodiesterase, all of which would retard the chances of developing symptoms of Alzheimer's disease.
Vitamin B5, or pantothenic acid, is used by the human body along with choline to form acetylcholine. Thus, as important precursors to the formation of acetylcholine, which is often present in reduced levels in Alzheimer's patients, choline and vitamin B5 are necessary nutritional supplements for preventing the onset of symptoms associated with neurodegenerative disorders, such as Alzheimer's.
Gamma tocopherol, an analog of vitamin E, has been proven to act as a strong antioxidant useful in the prevention of the symptoms of Alzheimer's disease in humans. Sesame lignans, preferably in the form of sesamolin, enhances the bioavailability of gamma tocopherol at the cellular level, thereby increasing the effectiveness of gamma tocopherol in combating the effects of the symptoms of Alzheimer's disease.
U.S. Pat. No. 6,572,899, issued to Gorsek on Jun. 3, 2003, describes a composition of orally ingestible nutrients for treating memory loss, dementia, and Alzheimer's disease. The '899 patent does not describe the use of curcumin and piperine to delay the onset of symptoms of Alzheimer's disease as does the applicant's application.
U.S. Pat. No. 6,486,194, issued to Ducharme et al., on Nov. 26, 2002, describes the use of enzyme inhibitors to disrupt the activity of cyclooxygenase to treat neurodegenerative diseases, including Alzheimer's disease. Although the '194 patent claims the oral administration of an enzyme inhibitor, the particular enzyme inhibited in that patent is not acetylcholinesterase, nor does the '194 invention describe the use of curcumin or piperine to retard the symptoms of Alzheimer's disease.
U.S. Pat. No. 6,646,013, issued to Barker et al., on Nov. 11, 2003, describes a composition including multiple nutrients for reducing the risk of colorectal cancer in mammals. The '013 patent claims the use of curcumin as one of the cancer-preventing nutrients, however, the '013 does not describe the use of curcumin for preventing the onset of the symptoms of Alzheimer's disease in humans.
U.S. Pat. No. 6,133,306, issued to Beal on Oct. 17, 2000, describes a method of inhibiting neurodegenerative diseases, including Alzheimer's disease, by administering nitroindazole to a patient to inhibit a neuronal oxide synthase. The '306 patent does not describe the use of curcumin or piperine to delay the onset of the symptoms of Alzheimer's disease in humans.